TY - JOUR
T1 - Contribution of caveolin protein abundance to augmented nitric oxide signaling in conscious dogs with pacing-induced heart failure
AU - Hare, Joshua M.
AU - Lofthouse, Robert A.
AU - Juang, George J.
AU - Colman, Laurence
AU - Ricker, Kelly M.
AU - Kim, Benjamin
AU - Senzaki, Hideaki
AU - Cao, Suyi
AU - Tunin, Richard S.
AU - Kass, David A.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2000/5/26
Y1 - 2000/5/26
N2 - Myocardial NO signaling appears elevated in heart failure (HF). Whether this results from increased NO production, induction of the high-output NO synthase (NOS)2 isoform, or changes in NOS regulatory pathways (such as caveolae) remains controversial. We tested the hypothesis that increased abundance of caveolin-3 and/or sarcolemmal caveolae contribute to increased NO signaling in pacing-induced HF. Abundance of caveolin-3 (0.59 ± 0.08 versus 0.29 ± 0.08 arbitrary units, P = 0.01) but not caveolin-1 was increased in HF compared with control conditions, assessed by Western blot. Additionally, transmission electron microscopy revealed increased caveolae (2.7 ± 0.4 versus 1.3 ± 0.3 per micrometer myocyte membrane, P<0.005). The association between caveolin-3 and NOS3 at the sarcolemma and T tubules was unchanged in HF compared with control myocytes. The impact of NOS inhibition with L-N(G)-methylarginine hydrochloride (L-NMMA) on β-adrenergic inotropy was assessed in conscious dogs before and after HF. In control dogs, dobutamine (5 μg · kg-1 · min-1) increased +dP/dt by 36 ± 7%, and this was augmented to 66 ± 24% by 20 mg/kg L-NMMA (P = 0.04 versus without L-NMMA, n = 8) but not affected by 10 mg/kg L-NMMA (34 ± 10%, P = NS; n = 8). In HF, dobutamine +dP/dt response was depressed (P<0.001 versus control), and increased concentrations were required to match control inotropic responses (10 to 15 μg · kg-1 · min-1, 48 ± 7%). L-NMMA enhanced +dP/dt responses similarly at 10 mg/kg (61 ± 17%, P = 0.02; n = 4) and 20 mg/kg (54 ± 7%, P = 0.04; n = 7). Caveolin-3 abundance positively correlated with L-NMMA augmentation of dobutamine inotropic responses in HF (r = 0.9, P = 0.03; n = 4). Thus, in canine pacing-induced HF, expression of caveolin-3 and of sarcolemmal caveolae is increased. This increase is associated with augmented agonist-stimulated NO signaling, likely via a compartmentation effect.
AB - Myocardial NO signaling appears elevated in heart failure (HF). Whether this results from increased NO production, induction of the high-output NO synthase (NOS)2 isoform, or changes in NOS regulatory pathways (such as caveolae) remains controversial. We tested the hypothesis that increased abundance of caveolin-3 and/or sarcolemmal caveolae contribute to increased NO signaling in pacing-induced HF. Abundance of caveolin-3 (0.59 ± 0.08 versus 0.29 ± 0.08 arbitrary units, P = 0.01) but not caveolin-1 was increased in HF compared with control conditions, assessed by Western blot. Additionally, transmission electron microscopy revealed increased caveolae (2.7 ± 0.4 versus 1.3 ± 0.3 per micrometer myocyte membrane, P<0.005). The association between caveolin-3 and NOS3 at the sarcolemma and T tubules was unchanged in HF compared with control myocytes. The impact of NOS inhibition with L-N(G)-methylarginine hydrochloride (L-NMMA) on β-adrenergic inotropy was assessed in conscious dogs before and after HF. In control dogs, dobutamine (5 μg · kg-1 · min-1) increased +dP/dt by 36 ± 7%, and this was augmented to 66 ± 24% by 20 mg/kg L-NMMA (P = 0.04 versus without L-NMMA, n = 8) but not affected by 10 mg/kg L-NMMA (34 ± 10%, P = NS; n = 8). In HF, dobutamine +dP/dt response was depressed (P<0.001 versus control), and increased concentrations were required to match control inotropic responses (10 to 15 μg · kg-1 · min-1, 48 ± 7%). L-NMMA enhanced +dP/dt responses similarly at 10 mg/kg (61 ± 17%, P = 0.02; n = 4) and 20 mg/kg (54 ± 7%, P = 0.04; n = 7). Caveolin-3 abundance positively correlated with L-NMMA augmentation of dobutamine inotropic responses in HF (r = 0.9, P = 0.03; n = 4). Thus, in canine pacing-induced HF, expression of caveolin-3 and of sarcolemmal caveolae is increased. This increase is associated with augmented agonist-stimulated NO signaling, likely via a compartmentation effect.
KW - Caveolae
KW - Compartmentation
KW - Heart failure
KW - Signal transduction
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U2 - 10.1161/01.RES.86.10.1085
DO - 10.1161/01.RES.86.10.1085
M3 - Article
C2 - 10827139
AN - SCOPUS:0034717034
VL - 86
SP - 1085
EP - 1092
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 10
ER -